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Rikkunshito Counteracts Total Gastrectomy-Induced Reductions in Food Intake and Weight By attenuating Glucagon-Like Peptide 1 Elevation in Rats
Masanobu Taguchi*1, Katsuya Dezaki2, Masaru Koizumi1, Kentaro Kurashina1, Yoshinori Hosoya1, Yasunaru Sakuma1, Hisanaga Horie1, Joji Kitayama1, Clarence Foster3, Alan K. Lefor1, Naohiro Sata1, Toshihiko Yada2
1Surgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan; 2Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan; 3Surgery, University of California, Irvine, School of Medicine, Orange, CA

Background & Aims: Total gastrectomy in patients with gastric cancer induces sustained weight loss, which can lead to reduced quality of life and increased mortality and may necessitate discontinuation of adjuvant chemotherapy. Rikkunshito, a Japanese traditional herbal medicine, has been reported to enhance orexigenic ghrelin action resulting in increased appetite. The aim of this study is to determine whether Rikkunshito increases food intake and weight in rats after gastrectomy, when there is no stomach to produce ghrelin.
Methods: Male Wistar rats underwent gastrectomy followed by roux-en-Y reconstruction or sham operation. Rikkunshito (1.2% weight/volume) was administered for 14 days starting on postoperative day three or 17, and daily food intake and weight measured. Rats were fed ad libitum and plasma ghrelin and glucagon-like peptide 1 (GLP-1) levels measured on postoperative days six and 10. A mixed meal tolerance test was conducted to assess plasma GLP-1 levels on days 10 and 24. Rats after gastrectomy or sham operation underwent continuous subcutaneous infusion of the GLP-1 receptor antagonist exendin (9-39) starting on day three. A pilot study measured pre- and postoperative plasma GLP-1 levels in five patients after total gastrectomy for gastric cancer.
Results: Administration of Rikkunshito starting on postoperative day three significantly increased food intake and weight (p<0.05), which continued for at least two weeks even after termination of treatment. Both fasting and postprandial plasma GLP-1 levels were markedly increased after gastrectomy compared to sham-operated rats (p<0.05) on day 10, and increased GLP-1 levels in rats after gastrectomy were significantly suppressed by Rikkunshito (p<0.05). Rikkunshito had no significant effect on plasma ghrelin levels after gastrectomy. Treatment with a GLP-1 receptor antagonist significantly improved food intake and weight after gastrectomy (p<0.05). Plasma GLP-1 elevation after gastrectomy was blunted on postoperative day 24, and RKT administered from day 17 had no effect on food intake or weight In patients, plasma fasting GLP-1 levels were significantly elevated after gastrectomy on postoperative day one (p<0.05).
Conclusions: Early, but not late, administration of Rikkunshito suppresses plasma GLP-1 elevation after total gastrectomy, which is associated with recovery from reduced food intake and weight in rats. Fasting plasma GLP-1 levels in patients after gastrectomy also increased, suggesting that these results may apply to humans.

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